Anti-human folate receptor beta antibodies and methods of use
Inventors
Low, Philip S. • Dimitrov, Dimiter S. • Feng, Yang • Shen, Jiayin
Assignees
Purdue Research Foundation • US Department of Health and Human Services
Publication Number
US-8871206-B2
Publication Date
2014-10-28
Expiration Date
2031-09-09
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Abstract
Human anti-human folate receptor beta (FRβ) antibodies and antigen-binding fragments thereof are described, as well as methods of using such antibodies and fragments to treat inflammatory disorders or cancers expressing cell surface FRβ.
Core Innovation
This invention provides human monoclonal antibodies and antigen-binding fragments thereof that specifically bind human folate receptor beta (FRβ). These antibodies reduce the number of FRβ positive cells in subjects and are useful for treating inflammatory disorders and cancers expressing cell surface FRβ. The antibodies are fully human, reducing the risk of immune responses and side effects compared with murine, chimeric, or humanized antibodies.
The antibodies or fragments can include defined heavy chain variable region complementarity determining regions (CDRs) and light chain variable region CDRs with specific amino acid sequences. They can bind to cell surface FRβ with high affinity and induce antibody-dependent cell-mediated cytotoxicity (ADCC) of FRβ expressing target cells. Some embodiments include de-fucosylated antibodies or fragments that do not detectably bind human folate receptor gamma (FRγ) or delta (FRδ). These antibodies can be conjugated with pharmaceutical agents, toxins, liposomes, or detectable moieties for therapeutic or diagnostic purposes.
There are methods disclosed for using these antibodies or fragments to treat patients having inflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and others, or cancers expressing FRβ such as acute myeloid leukemia or chronic myeloid leukemia. Methods include administering effective amounts of antibodies to reduce FRβ positive macrophages, monocytes, or cancer cells. The antibodies specifically bind to FRβ on activated macrophages and monocytes, which express FRβ upon activation, and thus can selectively target pathological cells while sparing quiescent cells.
Claims Coverage
The patent contains one independent claim describing an isolated human monoclonal antibody or antigen-binding fragment specifically binding human FRβ, with several dependent claims elaborating on specific properties and conjugations. The main inventive features focus on the antibody composition, binding properties, functional activities, and conjugation possibilities.
Specific binding to human FRβ with defined CDR sequences
The antibody or antigen-binding fragment comprises heavy chain variable region (VH) complementarity determining regions (CDR) 1, 2, and 3 comprising amino acid sequences set forth in SEQ ID NOs:1, 2, and 3 respectively, and light chain variable region (VL) CDR 1, 2, and 3 comprising amino acid sequences set forth in SEQ ID NOs:14, 15, and 16 respectively.
Selective binding properties and functional activities
The antibody or fragment has one or more properties including no detectable binding to human folate receptor alpha (FRα), binding to human but not mouse macrophages, a binding affinity of 20 nM, a dissociation constant (Kd) of 6.39 nM, and induction of antibody-dependent cellular cytotoxicity (ADCC) of FRβ-expressing target cells.
Binding to cell surface FRβ and IgG1 class antibody
The antibody or fragment binds to cell surface FRβ and can be an IgG1 antibody subclass.
De-fucosylation of antibody or fragment
The antibody or antigen-binding fragment can be de-fucosylated to enhance functional activity.
Conjugation with pharmaceutical agents, liposomes, toxins, or detectable moieties
The antibody or fragment can be conjugated with pharmaceutical agents (e.g., chemotherapeutics), linked to liposomes containing pharmaceutical agents, covalently linked to toxins, or linked to detectable moieties such as fluorescent, luminescent, radioactive labels, CT or MRI contrast agents, or biotin.
Compositions including the antibody or fragment with pharmaceutically acceptable carriers
Pharmaceutical compositions comprising the antibody or fragment and a pharmaceutically acceptable carrier are claimed.
The independent claim defines a human monoclonal antibody or fragment with specific CDR sequences that binds human FRβ selectively, possesses defined binding affinities and biological activities such as ADCC, and can be modified or conjugated for therapeutic or diagnostic applications. The dependent claims specify antibody subclass, modifications to enhance activity, various conjugation strategies, and pharmaceutical compositions comprising the antibody.
Stated Advantages
The antibody is fully human, reducing risks of immune responses and side effects compared with murine, chimeric, or humanized antibodies.
Specific binding to FRβ allows differential targeting of activated macrophages, monocytes, and FRβ-expressing cancer cells while sparing related folate receptors.
De-fucosylation or other modifications can enhance Fc receptor binding and increase antibody-dependent cellular cytotoxicity (ADCC).
Conjugation with pharmaceuticals, toxins, or detectable moieties enables targeted delivery of therapeutics or diagnostic agents, minimizing off-target effects.
Documented Applications
Treatment of inflammatory disorders including atherosclerosis, ischemia/reperfusion injury, transplantation rejection, vasculitis, inflammatory osteoarthritis, glomerulonephritis, restenosis, systemic sclerosis, fibromyalgia, sarcoidosis, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, psoriasis, Type 1 diabetes, Crohn's disease, multiple sclerosis, and Sjogren's disease.
Treatment of cancers expressing cell surface FRβ including myeloid cancers such as acute myeloid leukemia (AML), chronic myeloid leukemia (CML), multiple myeloma, or solid tumors with FRβ expression such as squamous cell carcinoma of the head and neck and non-epithelial malignancies.
Depletion of activated macrophages from human subjects to reduce disease-causing FRβ positive cells.
Use in methods for reducing severity or progression of inflammatory disorders or cancer by administering an effective amount of antibody or fragment to reduce numbers of FRβ positive cells.
Diagnostic or monitoring use by conjugating antibodies to detectable moieties such as fluorescent, luminescent, radioactive labels, or contrast agents.
Production of engineered T cells expressing chimeric immune receptors including an anti-FRβ scFv fused to intracellular signaling domains for targeted killing of FRβ expressing cells.
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